Many of the large, publicly accessible commercial libraries are based on planar heterocyclic aromatic scaffolds that lack variety as pharmacophores in terms of three dimensional space filling and conformational mobility. As such, the Pilot Library Program of the NIH was created to pursue unique chemical diversity not represented by currently available libraries. Natural products have been mined for centuries to fulfill the need for bioactive substances and currently comprise a large proportion of clinically used drugs. By definition, natural products are inherently biased towards biological availability and activity, and libraries derived there from possess unique three-dimensional structural features and are more complex than simpler compounds derived from purely synthetic reagents. Hence, we plan to take advantage of unique, commonly available natural product templates for the preparation of new libraries that are underrepresented in current commercial libraries and the Molecular Library Small Molecule Repository (MLSMR). The specific aims of this program include strategic diversity-oriented elaboration of readily accessible natural product nucleoside scaffolds. We will prepare 1400 highly pure and novel samples from the three specific aims and supply between 10 to 20 mg of each sample as dry powders to the MLSMR as per program requirements. These samples will be carefully screened to guarantee that they are not covered through patents in order to ensure unencumbered usage, and all data on the samples (synthetic methods and analyses) will be made freely accessible to the scientific community as per NIH Resource Sharing requirements. The enrichment of the chemical diversity of the NIH MLSMR should enhance the prospect of identifying biochemical tools to probe a variety of biological targets of relevance in health and disease. Moreover, the screening of the libraries and free accessibility of those data will stimulate research that should ultimately lead to improvements in our knowledge of systems biology and the living organism. Advances from this effort may eventually lead to new therapeutics, especially for rare or marginalized disorders thus benefiting overall public health.